Human cytomegalovirus (HCMV) belongs to the herpesvirus group and is found universally throughout all geographic locations and socioeconomic groups. While it infects between 50 and 85% of adults, for most healthy persons who acquire primary HCMV after birth, there are no long-term consequences.
However, there are clinical situations where HCMV infection is a significant cause of morbidity and mortality. For example, HCMV infection carries significant health risks to a foetus in utero, to people who work with children, and to individuals having a compromised immune system, eg. those infected with HIV-1 or having undergone organ transplantation (Britt, 1996, Trends Microbio 4 34; Plotkin, 1999, Pediatr Infect Dis J 18 313).
Epidemiological studies have shown that 80 to 90% of developing unborn babies who acquire congenital HCMV infection display a variable pattern of pathological sequelae within the first few years of life that may include hearing loss, vision impairment and mental retardation.
Accordingly, there is a need for an effective vaccine to provide such a reduction in HCMV load within the population. To this end, there have been a number of such attempts using either attenuated HCMV strains or subunit vaccines (as reviewed by Britt, 1996, supra; Plotkin, 1999, supra).
Initial vaccines were based on immunisation using attenuated strains of HCMV, eg., the Towne and AD-169 strains (Elek & Stern, 1974, Lancet 1 1-5, 1974; Neff et al., 1979, Proc Soc Exp Biol Med 160 32). The issue of whether a HCMV vaccine should invoke both humoral and cellular arms of the immune system is of considerable interest and although both attenuated viruses were shown to elicit these responses, neither vaccine prevented foetal infection in pregnant women experiencing a primary HCMV infection. Furthermore, vaccinated normal volunteers showed limited protection from vital challenge using the HCMV Toledo strain (Quinnan et al., 1984, Ann Intern Med 101 478; Alder et al., 1998, Pediatr Infect Dis J. 17 200).
Subsequent vaccine development has included subunit vaccines which are based on single HCMV antigen formulations, eg. by using the full-length glycoprotein B (gB) polypeptide in combination with MF59 adjuvant (Chiron), or alternatively, a recombinant full-length gB polyepitope protein expressed using a viral vector (Pass et al., 1999, J Infect Dis 180 970; Alder et al., 1999, J Infect Dis 180 843). Additionally, a canarypox virus expressing a full length recombinant HCMV pp65 polyepitope has been tested in a clinical trial and shown to elicit a strong CTL and antibody response to this antigen (Gyulai et al., Proceedings of the Seventh International Cytomegalovirus Workshop, Brighton, UK, Mar. 7-9, 1999, abstract). However, vaccine formulations based on one or more full-length HCMV antigens are likely to present a number of limitations in that normal cellular processing is interrupted, thereby affecting epitope presentation. For example, the expression of HCMV proteins such as pp65 can inhibit proteasomal processing of IE-1 through an associated kinase activity (Gilbert et al., 1996, Nature 383, 720).
An alternative approach for producing CTL responses, as described in WO 03/000720, has been to combine a plurality of epitopes from various antigens to form a polyepitope construct and thereby avoid the use of full-length antigens altogether.